Magnetic resonance imaging (MRI) provides a method for non-invasively obtaining diagnostic images of the body. MRI is now an indispensable diagnostic tool, and methods for improving the quality of the image produced are needed to facilitate image interpretation and provide additional diagnostic information.
A. External Contrast Agents
Conventional MRI images of biological tissues reflect a combination of spin-lattice (T1) and spin-spin (T2) water proton relaxation. Externally administered contrast agents, which enhance the relaxation rate of water protons, have been developed to enhance natural MRI contrast. Commonly used external contrast agents include paramagnetic chelated metal ions, such as gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) and chelated metal Gd-DOTA. Casali et al., Acad. Radiol., 5:S214-8, (1998). The usefulness of these metal chelates as contrast agents for in vivo imaging is substantially limited by toxicity and T2 effects.
As an alternative to metal ions, other external MRI contrast agents, including iopamidol, arginine, serine and glycine, have been examined for their ability to enhance contrast in vitro. Aime et al., Invest. Radiol., 23:S267-70 (1988). These external contrast agents enhance MRI contrast by decreasing the T2 signal, which is not very specific and can be influenced by many factors.
B. Saturation Transfer
Previous studies showed that by saturating protons of small metabolites (i.e. ammonia) that can undergo chemical exchange with other materials, such as water, an associated decrease in the intensity of the water proton signal resulted in a several-order magnitude increase in sensitivity compared to direct detection. Wolff and Balaban, J. Magn. Reson., 86:164 (1990). This observation demonstrated that proton exchange can be imaged using saturation transfer methods in vitro.
Proton chemical exchange between water and metabolites is a common process in biological tissues. Metabolite/water proton chemical exchange can range from fast-to-intermediate-to-slow, depending on the chemistry of the exchange sites, temperature, pH and other factors. Strategies have been presented to image the distribution of chemical exchange using saturation transfer (ST) in the magnetization preparation period of an imaging sequence. Hsieh and Balaban, J. Mag. Res., 74: 574 (1987); McFarland et al., Mag. Reson. Imag., 6:507 (1988); Wolff and Balaban, J. Magn. Reson., 86:164 (1990). ST is most effective under slow-to-intermediate exchange conditions where the exchanging spins can be adequately resolved and sufficient exchange occurs between the molecules, relative to T1, to detect transfer of the saturated protons. This limitation reduces the number of reactions that can be detected with ST; however, it may improve the specificity of the measurement in complex biological tissues.
C. Intrinsic Tissue Contrast and ST
Saturation transfer methods known prior to the present invention rely primarily on the patient's intrinsic macromolecules as the sole source of bound protons. The presence of ethanol also has been used to provide for an alternative source of bound protons. Govindaraju et al., Alcohol and Alcoholism, 32(6):671-681 (1997); Meyerfhoff et al. Alcoholism: Clinical and Experimental Research, 20(7):1283-1288 (1996). The effect observed by these authors is due to dipolar interactions between water protons and free ethanol protons, not chemical exchange. Distinguishing bound protons from free protons in vivo is complex, making irradiation of solely bound protons difficult. In addition, although the intrinsic macromolecules of some tissues readily undergo proton chemical exchange, other tissues do not. These factors have limited MRI contrast enhancement.
Nevertheless, intrinsic tissue contrast and saturation transfer have been used for imaging, For example, Balaban et al., U.S. Pat. No. 5,050,609, which is incorporated herein by reference, describes using saturation transfer to enhance MRI contrast of tissues, polymers and geological samples. Wolff and Balaban demonstrated exchange between irradiated bound protons with free protons using MRI saturation transfer methods in vivo. Wolff and Balaban Magn. Reson. Med., 10:135-144 (1989). The maximum amount of decrease observed in the free proton pool was 70%. This decrease was observed only in certain tissues, such as the rabbit kidney. Kajander et al. observed the greatest MRI contrast enhancement in striated muscle, but only modest enhancement in the liver, kidney cortex and spleen. Kajander et al., Magn. Reson. Imag., 4:413-7 (1996). Thomas used saturation transfer to improve the details of small vessel angiography to increase the contrast of breast and brain lesions, and to provide greater details of the knee and cervical spine. Thomas, Radiol. Technol., 67:297-306 (1996).